The menisci are C-shaped fibrocartilage disks that occupy the periphery of the knee joint and serve a number of significant mechanical functions including load distribution across articular cartilage, and joint stabilization. In the face of such mechanical demands, it is not surprising that the meniscus can become damaged. Unfortunately, surgical options for the treatment of damaged menisci are limited, primarily due to the poor vascularity and healing capacity of the central two thirds of the meniscus. Allograft implantation is complicated by the threat of transmission of infectious diseases, the difficulty of matching meniscal shape and material properties, and problems with maintaining cell viability. While meniscectomy (the complete or partial removal of the affected tissue) which is the most common orthopedic procedure performed in the United States can lead to the early onset of osteoarthritis. Providing a meniscal substitute engineered to function much in the way of the native tissue could delay or even avoid the onset of osteoarthritis. Meniscal substitutes, whether cell-seeded degradable scaffolds or synthetic implants, should ideally help to distribute loads across adjacent articular cartilage much in the way of the native tissue, thereby protecting the underlying articular cartilage. However, the properties of a substitute that are required to ensure that this functional capability is met are unclear. This is caused in part by the absence of a robust, comprehensive and physiologically relevant model within which the effect of substitute design variables can be parametrically studied. This lack of such a test, or series of tests, makes the design and evaluation of candidate scaffolds impossible, retards the regulatory pathway to commercialization, and leads to a situation where scaffolds are implanted in humans with little information about their ability to perform mechanically in the highly-loaded environment of the knee joint. Our goal is to define the relationship between meniscal substitute material and structural properties and joint contact mechanics under multiple physiological activities across a range of patient populations. The main element of the framework required to achieve this goal is a statistically-based, rapidly computable interpolator that will be built using results from experimentally-validated knee specific computational models. We will gather information about factors that most markedly affect the functional performance of the native meniscus and use this information as a template to identify the design space into which substitutes should fall if they are to function appropriately. Our goal is not to design a meniscal substitute;rather, we will demonstrate that our approach can establish a workable design space for use by those developing solutions for meniscal repair. Our efforts will culminate in the development of a new paradigm for the development and screening of any complicated tissue substitute, whether a non-degradable implant or a cell-seeded degradable scaffold prior to initiating more time consuming and costly animal and clinical trials. PUBLIC HEALTH RELEVANCE: Our goal is to define the relationship between meniscal material and structural properties and joint contact mechanics under multiple physiological activities across a range of patient populations. The main element of the framework required to achieve this goal is a statistically-based, rapidly computable interpolator that will be built using results from experimentally-validated computational models of the intact and meniscal substituted knee. Our approach will serve as a tool for rapid evaluation and design of functional substitutes and provide a new paradigm for the development and screening of any complicated tissue substitute, whether a non- degradable implant or a cell-seeded degradable scaffold.